2-187502129-A-G

Position:

• chr2-187502129-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006287.6(TFPI):​c.121+1519T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 152,296 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.038 (175 hom., cov: 32)
• Consequence: TFPI NM_006287.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.551

Genes affected

TFPI (HGNC:11760): (tissue factor pathway inhibitor) This gene encodes a Kunitz-type serine protease inhibitor that regulates the tissue factor (TF)-dependent pathway of blood coagulation. The coagulation process initiates with the formation of a factor VIIa-TF complex, which proteolytically activates additional proteases (factors IX and X) and ultimately leads to the formation of a fibrin clot. The product of this gene inhibits the activated factor X and VIIa-TF proteases in an autoregulatory loop. Inhibition of the encoded protein restores hemostasis in animal models of hemophilia. This gene encodes multiple protein isoforms that differ in their inhibitory activity, specificity and cellular localization. [provided by RefSeq, Jul 2016]

CALCRL-AS1 (HGNC:55863): (CALCRL and TFPI antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.087 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFPI	NM_006287.6	c.121+1519T>C		intron_variant		ENST00000233156.9	NP_006278.1
CALCRL-AS1	XR_007087504.1	n.3519+2524A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFPI	ENST00000233156.9	c.121+1519T>C		intron_variant		1	NM_006287.6	ENSP00000233156	P1
CALCRL-AS1	ENST00000412276.6	n.289+2524A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 5765 AN: 152176 Hom.: 175 Cov.: 32

Gnomad AFR AF: 0.00852

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0909

Gnomad ASJ AF: 0.0446

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0510

Gnomad OTH AF: 0.0454

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0379 AC: 5767 AN: 152296 Hom.: 175 Cov.: 32 AF XY: 0.0370 AC XY: 2756 AN XY: 74456

Gnomad4 AFR AF: 0.00849

Gnomad4 AMR AF: 0.0909

Gnomad4 ASJ AF: 0.0446

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.0167

Gnomad4 NFE AF: 0.0510

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.0444 Hom.: 44

Bravo AF: 0.0423

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.46
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs8176597; hg19: chr2-188366856;